Non-melanoma skin cancers (NMSC) are the most common form of cancer in humans, with over 1 million new cases identified in the United States each year. In fact, more Americans will be diagnosed with some form of skin cancer than all other cancers combined. Epidemiological studies have shown that there are gender differences in the development of NMSC, with men being as twice as likely to NMSC in general and three times as likely to develop squamous cell carcinomas as women. This disparity has been attributed to lifestyle choices, since males historically have had professions requiring more time out in the sun and are less likely to use sun protection. However, no studies had determined if gender differences in skin tumor development occur when males and females receive equivalent cumulative UV exposure. Recent studies from our laboratory suggest that the pathways by which UV exerts its damaging effects in male and female skin are not the same and that blocking UV-induced inflammation in male skin may not be as effective in decreasing tumor development as in female skin. The primary goals of the proposed studies are to determine the underlying mechanistic differences in the UVB response of male and female skin and to identify differences between the genders in initiation, promotion and progression of UV-induced SCC. Two specific aims are proposed to test the hypothesis that decreased levels of antioxidant activity, increased reactive oxygen species (ROS) production and increased oxidative DNA damage in male skin not only influence the acute cutaneous response to UVB exposure but also contribute to the observed gender disparity in the development of NMSC. Studies in Specific Aim 1 will determine the differential contribution of antioxidants and inflammation generated reactive oxygen species to DNA damage in unirradiated skin and during an acute UVB-induced inflammatory response in male and female Skh-1 murine skin. Studies in Specific Aim 2 are designed to determine the differential chemopreventive effects of topical treatment with an antioxidant (vitamin E), an anti-inflammatory drug (celebrex), a natural antioxidant/anti-inflammatory agent (Black Raspberry extract) or a combination of the two on UV induced tumor initiation, promotion and progression in male vs. female Skh-1 mice. A clearer understanding of the differences in the skin of males and females will ultimately allow for the development of more appropriately targeted prevention and treatment strategies. PUBLIC HEALTH RELEVANCE: Exposure to Ultraviolet light is believed to be the single most important etiological factor in the development on skin cancer. Epidemiological studies have shown that there are gender differences in the development of nonmelanoma skin cancer (NMSC) with men being as twice as likely to develop NMSC and three times as likely to develop squamous cell carcinoma as women. This disparity has been attributed to lifestyle choices, since males historically have had professions requiring more time out in the sun and are less likely to use sun protection. Recent studies from our laboratory using the Skh-1 mouse model have demonstrated inherent biological differences in the skin of males and females. The studies in the current proposal are designed to understand the differential response of male and female skin to both acute and chronic ultraviolet light exposure. A clearer understanding of the differences in the skin of males and females will ultimately allow for the development of more appropriately targeted prevention and treatment strategies for this most common form of cancer in humans.